A fundamental and crucial aspect of normal development of the CNS is regulation of oligodendrocyte proliferation. It may also be involved in several neuropathological conditions and be a critical factor in failure of recovery in demyelinating disorders and CNS regeneration. We hypothesize that in addition to hormonal and other systemic regulation of oligodendrocyte proliferation, neuron-oligodendrocyte interactions play a critical role in the development of oligodendrocytes, that this interaction is mediated in part by soluble factors derived from neurons, and that the target cells for neuronal-derived growth factors are glial precursor cells. We have identified a factor produced by a CNS neuronal cell line that stimulates division of oligodendrocytes and inhibits division of Type I astrocytes in dissociated neonatal rat brain cultures. We will purify this factor using chromatographic produces and a sensitive ELISA bioassay, characterize the chemical properties of the factor, determine whether the oligodendrocyte-stimulating and astrocyte-inhibiting factors are identical, define the target cells for the oligodendrocyte growth factor with the aid of differentiation stage-specific antibodies and tritiated thymidine autoradiography, and verify that developing CNS contains a factor with similar properties. In parallel we will develop monoclonal antibodies to the growth factor using in vitro immunization methods and screening for neutralization of factor activity. The monoclonal antibody will be used for immunoaffinity chromatography in future purifications of the factor and for detecting the presence of antigen and its cellular localization in the developing rat nervous system. Our results should provide information about oligodendrocyte cell lineage in the brain and the capability of cells within this lineage to divide in response to a neuronal-derived growth factor. This data will be relevant to normal developmental processes and may provide insight into ways to accelerate recovery from demyelinating disorders.
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